DESCRIPTION: Carbon tetrachloride (CCl4) induces liver injury, which involves many pathological processes. In response to injury, the liver has the unique ability to regenerate. Signals that regulate liver regeneration must include factors that inhibit cell division when liver mass is restored. The cyclin kinase inhibitors (CKIs) p21 and p27 are potent inhibitors of cyclin dependent kinases, and their overexpression can inhibit cell cycle progression. Dr. Tyner's preliminary data indicate that both p21 and p27 are differentially regulated in the liver following CCl4 treatment. Expression of both factors is first localized to hepatocytes that will die following metabolism of CCl4. At later time points, p21 and p27 are expressed specifically in periportal hepatocytes that have replicated to restore liver mass. Dr. Tyner hypothesizes that localized expression of p21 and p27 during early G1 may represent a checkpoint that prevents damaged cells from replicating and that the two CKIs regulate the extent of liver growth at later time points. Both p21 and p27 have been reported to play roles in regulating apoptosis, and it is possible that localized induction of these CKIs will also influence mechanisms of cell death. Decreased expression of p21 and p27 has been detected in human cancers and lack of these critical cell cycle checkpoint proteins may lead to increased susceptibility to development of liver tumors following liver injury. These hypotheses will be tested by examining regeneration and cell death in wildtype and CKI knockout mice. The p21 gene is responsive to a wide array of extracellular signals and its expression is induced in pericentral hepatocytes a short time following administration of CCl4. Identifying factors responsible for inducing p21 gene expression in response to CCl4, will lead to further insight about cellular signaling cascades initiated by hepatotoxins.